1. Technical Field
This invention relates to a process of making heteroaryl amine intermediates.
2. Background Information
Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine production and effective therapeutics in cytokine-mediated diseases including inflammatory and autoimmune diseases. Examples of such compounds are reported in U.S. Pat. Nos. 6,080,763 and 6,319,921, and WO 00/55139 including aryl- or heteroaryl-substituted ureas.
In U.S. Pat. No. 6,358,945 the synthesis of II, a preferred intermediate, was described as illustrated in Scheme 1.

The synthesis begins with a palladium catalyzed carbonylation of 2,5-dibromopyridine (III) to provide ester IV in 55% yield. The reaction is run under pressure (80 psi CO) and must be monitored to minimize formation of the diester, an unwanted by-product. Reduction of IV with diisobutylaluminum hydride at −78° C. provides aldehyde V. This is followed by reductive amination to give VI.
Intermediate VI is then converted to II by reaction with t-BuLi at −78° C. followed by tributyltin chloride to give tributylstannane VII, followed by palladium catalyzed Stille coupling with intermediate VIII to give II. Conversion of VI and analogous intermediates to other intermediates of formula II via Suzuki coupling is also described in U.S. Pat. No. 6,358,945 (Scheme 2). According to this method, intermediate IX is treated with n-BuLi followed by trimethylborate to give arylboronic acid X. Palladium catalyzed Suzuki coupling with VI provides XI, which is deprotected by treatment with acid to give II.

This process is not well-suited for large-scale and commercial use for several reasons. One reaction (Scheme 1) is run under high pressure (80 psi) and another at extreme temperature (−78° C.). The yield of IV is only moderate and by-product formation requires a purification step. These factors, plus the cost of starting materials and reagents make this process too costly for commercial scale.
U.S. Pat. No. 6,635,767 discloses a process of making compound II above involving reacting 2-(5-halopyridyl) magnesium halides 3, with an in situ generated immonium salt electrophile 6 as shown below in Scheme 3, or alternatively by reacting with a formyl bearing group e.g. 7.

Reaction intermediate 4 is then reacted with 9 as can be seen in Scheme 4 which also shows the conversion of 7 to 9.

Other related reactions can be found in WO 01/32627, WO 02/083642, Miyaura, N.; Suzuki, A. Chem Rev. 1995, 95, 2457-83; Suzuki, A. in Metal-catalyzed Cross-coupling Reactions; Diederich, F,; Stang, P. J. Eds. Wiley-VCH: Weinheim, Germany, 1998, chapter 2, 49-97.